JP2020504140A - Phosphaplatin compounds as therapeutics for the treatment of bone or blood cancer - Google Patents

Abstract

(Pyrophosphato) platinum (II) or (pyrophosphato) platinum (IV) complexes ("phosphaplatin compounds"), especially (R, R) -1,2-cyclohexanediamine- (dihydrogenpyrophosphato) platinum (II) (or The use of "PT-112") as a therapeutic agent for the treatment of bone and blood cancers or cancer that metastasizes to the bone, and methods thereof are disclosed.

Description

CROSS REFERENCE TO RELATED APPLICATIONS S. C. Under §119 (e), the benefit of US Provisional Application No. 62 / 443,416, filed January 6, 2017, is hereby incorporated by reference in its entirety.

  The present invention relates to the use of phosphaplatin compounds as therapeutic agents for the treatment of bone cancer or hematological cancer and methods thereof.

  Bone is composed of bone-like (hard) tissue, cartilage (strong and soft) tissue, and fibrous (filamentous) tissue, as well as bone marrow elements. Bone cancer can occur in any bone and any type of bone tissue in the body. If found early, bone cancer can be treated by surgery to remove the tumor and cancerous cells, if the tumor and cancerous cells are not spread and can be removed cleanly. Especially ideal. In many cases, treatment requires a combination of surgery with other treatments, such as stem cell transplantation, chemotherapy, radiation therapy, and the like. Targeted chemotherapy for the treatment of bone cancer, in principle, requires that chemotherapeutic agents accumulate in cancerous bone tissue after systemic administration. This requirement, along with the wide variety of bone cancer, makes developing bone cancer treatments a daunting task.

  Hematological cancers (or hematological cancers) are closely related to bone cancer because they arise in hematopoietic tissues, such as bone marrow, or cells of the immune system. Examples of hematological cancers are leukemia, lymphoma, and multiple myeloma. In particular, multiple myeloma, a neoplastic plasma cell disorder characterized by clonal expansion of malignant plasma cells in the bone marrow microenvironment, monoclonal proteins in blood or urine, and associated organ dysfunction, is a neoplastic disease. It accounts for about 1% and 13% of blood cancers. (Palumbo, A. and Anderson, K .; "Multiple Myeloma," New. Engl. J. Med., 2011, 364 (11): 1046-1060). Treatments for multiple myeloma, including alkylating agents, glucocorticoids, immunomodulators (IMiDs), and proteasome inhibitors have been developed (Chesi, M., et al., Blood, 2012, 120 (2 , 376-385), multiple myeloma is still considered a deadly B-cell malignancy (US2013 / 0281377A1).

  Platinum-based antineoplastic agents such as cisplatin, carboplatin, and oxaliplatin do not contain alkyl groups, but may be described as "alkylated-like" due to similar effects as their alkylated antineoplastic agents (Cruet-Hennequart, S., et al. DNA Repair (Amst.), 2008, 7 (4): 582-596). They have been used to treat a variety of cancers, including ovarian, testicular, small cell lung, and colorectal.

  Both R. Bose, U.S. Patent Nos. 7,700,649 and 8,034,964, a new class of platinum-based antitumor agents, namely "phosphaplatin" complexes, which contain a pyrophosphate group. ) Functions as an anticancer agent without resorting to covalently binding to DNA. As a result, they were found to be effective in treating various cisplatin- and carboplatin-resistant cancers. These phosphaplatin compounds have a pyrophosphate moiety in these compositions, which allows these anticancer agents to be derived from, present in, or metastatic to bone. It is speculated that they can be selective for targeting cancer.

  Examples of such diseases include prostate cancer or other solid tumor cancers that tend to metastasize to bone, and multiple myeloma or other hematological malignancies of bone origin.

US2013 / 0281377A1 US Patent No. 7,700,649 US Patent No. 8,034,964

Paulumbo, A .; and Anderson, K .; "Multiple Myeloma," New. Engl. J. Med. , 2011, 364 (11): 1046-1060. Chesi, M .; , Et al. , Blood, 2012, 120 (2), 376-385. Cruet-Hennequart, S .; , Et al. DNA Repair (Amst.), 2008, 7 (4): 582-596.

  The present application is based on the surprising discovery that these pyrophosphato-platinum complexes can accumulate in bone tissue of treated mice and can effectively reduce M spike levels in established multiple myeloma mouse models. Disclosed are methods of treating bone or blood cancers or cancers that metastasize to bone using phosphaplatin compounds.

  The method comprises administering a therapeutically effective amount of a compound according to any one of Formulas I-IV, or a pharmaceutically acceptable salt thereof, or a composition thereof, to a subject having bone or blood cancer. Including or consisting essentially of:

Wherein R ¹ and R ² are each independently selected from NH ₃ , substituted or unsubstituted aliphatic amines, and substituted or unsubstituted aromatic amines, and R ³ is a substituted or unsubstituted aliphatic diamine; And substituted or unsubstituted aromatic diamines.

  In some preferred embodiments, the phosphaplatin compound is a 1,2-cyclohexanediamine- (dihydrogen pyrophosphato) platinum (II) ("pyrodach-") having a structure of a formula selected from the group consisting of: 2 ")

These are trans- (R, R) -1,2-cyclohexanediamine (pyrophosphato) platinum (II) ("(R, R) -pyrodac-2") and trans- (S, S) -1,2, respectively. -Cyclohexanediamine (pyrophosphato) platinum (II) ("(S, S) -pyrodac-2"), and cis-1,2-cyclohexanediamine (pyrophosphato) platinum (II) ("cis-pyrodac-2"). is there.

  In another embodiment, the present invention relates to any of the phosphaplatin compounds disclosed herein or a pharmaceutical thereof in the manufacture of a medicament for the treatment of bone or blood cancer or cancer that metastasizes to bone. Including the use of chemically acceptable salts.

  Other aspects and advantages of the present invention will be better understood in view of the following drawings, description, and claims.

FIG. 2 illustrates the change in M spike levels in transgenic Vk * Myc mice treated with (R, R) -Pyrodac-2. 2 illustrates the change in survival level in mice treated with (R, R) -Pyrodac-2. FIG. 3 illustrates the change in M-spike levels in mice treated with (R, R) -Pyrodac-2. 24 illustrates ICP-MS imaging of the screened area (white bars) of mice treated with (R, R) -Pyrodac-2 24 hours later. 7 illustrates the detection of platinum in liver in treated mice at T24 hours (raw data). 3 illustrates three section plans of treated mice for ICP-MS imaging for the detection of platinum in mice. 5 illustrates the good linearity of Pt by spotting a calibration standard on a liver control tissue section. Figure 5 shows a quantified imaging map based on LA-ICP-MS analysis of platinum in treated mice in T45 min section plan 1. Figure 5 shows a quantified imaging map based on LA-ICP-MS analysis of platinum in treated mice in T45 min section plan 2. Figure 4 shows a quantified imaging map based on LA-ICP-MS analysis of platinum in treated mice in T45 min section plan 3. Figure 4 shows a quantified imaging map based on LA-ICP-MS analysis of platinum in treated mice in T24 hour section plan 1. Figure 3 shows a quantified imaging map based on LA-ICP-MS analysis of platinum in T45 minute treated mice in a bone containing compartment. Figure 2 shows (R, R) -Pyrodac-2-induced decrease in PSA in mCRPC patients. FIG. 4 shows (R, R) -Pyrodac-2-induced decrease in serum alkaline phosphatase in mCRPC patients. (R, R) -Pyrodac-2-induced decrease in SUV signal at metastatic bone disease sites in metastatic basal cell carcinoma patients.

  The present invention is based on the finding that phosphaplatin complexes administered to mice can accumulate, inter alia, in bone tissue of mice, and this complex, like multiple myeloma, as shown in reputable mouse models. It is based on the surprising discovery that it can be used to effectively treat various bone / blood cancers and to treat cancer that has spread to bone tissue.

  In one aspect, the invention provides administering to a subject a therapeutically effective amount of a phosphaplatin compound having a structure of Formula I or II, or a pharmaceutically acceptable salt thereof, wherein the subject has a bone cancer or blood. Provide a way to treat cancer

Wherein R ¹ and R ² are each independently selected from NH ₃ , substituted or unsubstituted aliphatic amines, and substituted or unsubstituted aromatic amines, and R ³ is a substituted or unsubstituted aliphatic diamine; And substituted or unsubstituted aromatic diamines.

  Bone or blood cancers include osteosarcoma, chondrosarcoma, Ewing tumor, malignant fibrous histiocytoma (MFH), fibrosarcoma (fibroblastic sarcoma), giant cell tumor, chordoma, spindle cell sarcoma, multiple Myeloma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, leukemia, pediatric acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML), hairy cell leukemia, juvenile myelomonocytic leukemia (JMML), myelodysplastic It can be selected from plastic syndrome, myelofibrosis, myeloproliferative neoplasm, polycythemia vera, thrombocythemia and the like.

  In some embodiments, the bone or blood cancer is osteosarcoma, chondrosarcoma, Ewing tumor, malignant fibrous histiocytoma (MFH), fibrosarcoma, giant cell tumor, chordoma, spindle cell sarcoma, multiple Selected from multiple myeloma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, leukemia and the like. In one preferred embodiment, the bone or hematological cancer is multiple myeloma.

In one embodiment of this aspect, R ¹ and R ² are each independently selected from NH ₃ , methylamine, ethylamine, propylamine, isopropylamine, butylamine, cyclohexaneamine, aniline, pyridine, and substituted pyridine; R ³ is selected from 1,2-ethylenediamine and 1, 2-diamine.

  In another embodiment of this aspect, the phosphaplatin compound is

Selected from the group consisting of their pharmaceutically acceptable salts, and mixtures thereof.

  In a preferred embodiment, the phosphaplatin compound is R, R-pyrodac-2 having the formula:

  In one aspect, the invention provides a method of treating a subject having a bone cancer or a hematological cancer, the method comprising: a therapeutically effective amount of a phosphaplatin compound having a structure of Formula III or IV, or a pharmaceutical thereof. Comprising administering to the subject a chemically acceptable salt,

Wherein R ¹ and R ² are each independently selected from NH ₃ , substituted or unsubstituted aliphatic amines, and substituted or unsubstituted aromatic amines, and R ³ is a substituted or unsubstituted aliphatic diamine; And substituted or unsubstituted aromatic diamines.

In one embodiment of this aspect, R ¹ and R ² are each independently selected from NH ₃ , methylamine, ethylamine, propylamine, isopropylamine, butylamine, cyclohexaneamine, aniline, pyridine, and substituted pyridine. , R ³ are selected from 1,2-ethylenediamine and cyclohexane 1,2-diamine.

In another embodiment of this aspect, the phosphaplatin compound has the formula (IV), wherein R ³ is 1,2-ethylenediamine or cyclohexane-1,2-diamine.

  In another embodiment of this aspect, the phosphaplatin compound is

Selected from the group consisting of their pharmaceutically acceptable salts, and mixtures thereof.

  In some embodiments, administration comprises intravenous or intraperitoneal injection.

  In some embodiments, administering comprises intravenous injection.

  In some embodiments, administration comprises intraperitoneal injection.

  In some embodiments, the dose of the platinum pyrophosphate complex ranges from about 1 mg to about 200 mg / Kg.

  In some embodiments, the method is used in conjunction with administering a second anti-cancer agent to the subject.

  In some embodiments, the second anticancer agent is selected from the group consisting of an alkylating agent, a glucocorticoid, an immunomodulator (IMiD), and a proteasome inhibitor.

  In another aspect, the present invention provides a phosphaplatin compound disclosed herein or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of bone cancer or blood cancer or cancer that metastasizes to bone. Including the use of any of these salts. In some embodiments, the phosphaplatin compound is selected from the group consisting of (R, R) -Pyrodac-2, (S, S) -Pyrodac-2, and cis-Pyrodac-2. In some embodiments, the phosphaplatin compound is selected from the group consisting of (R, R) -Pyrodac-4, (S, S) -Pyrodac-4, and cis-Pyrodac-4. In a preferred embodiment, the phosphaplatin compound is (R, R) -pyrodac-2 (or “PT-112”).

  The terms used in the description of the invention herein are for the purpose of describing particular embodiments only, and are not intended to limit the invention. As used herein, the singular forms "a," "an," and "the" are intended to include the plural forms as well, and vice versa, unless the context clearly indicates otherwise. The same is true.

  The term "about" as used herein is intended to mean up to ± 10% of the indicated value. It is to be understood that any range mentioned in this specification or in the claims includes the range itself and anything subsumed therein, including both endpoints.

  The terms "subject" or "patient" as used herein generally refer to mammals, including humans, and animals, such as dogs, cats, horses, and the like.

  The terms "composition", "pharmaceutical composition", or "pharmaceutically acceptable composition" refer to a phosphaplatin compound and at least one pharmaceutically acceptable carrier, diluent, adjuvant, and vehicle. And inert ingredients, which are generally inert, non-toxic, solid or liquid fillers that do not react with the phosphaplatin complex, as is known in the art. , Diluents, or encapsulating materials.

  The phosphaplatin compound, a pharmaceutical salt thereof, or a complex thereof can be administered in various ways, for example, orally, subcutaneously, or intravenously, intraarterially, intramuscularly, intraperitoneally, intratonally, And parenteral administration, including intranasal and intrathecal and infusion techniques. Pharmaceutical formulations containing phosphaplatin containing any suitable carrier, such as various vehicles, adjuvants, excipients, and diluents, can be administered to patients in injectable formulations. See, for example, WO 2017/176880, which is incorporated herein by reference in its entirety. For parenteral administration, they will generally be formulated in a unit dosage injectable form (eg, solution, suspension, emulsion). Pharmaceutical formulations suitable for injection include sterile aqueous solutions or dispersions and sterile powders for reconstitution into sterile injectable solutions or dispersions. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. Sterile injectable solutions can be prepared, if desired, by incorporating the phosphaplatin complex in the required amount of a suitable solvent with one or more other ingredients.

  The present disclosure is intended to cover any dose of a phosphaplatin compound that can provide a therapeutic benefit to a subject having any bone or blood cancer, but based on the weight of the subject It is disclosed that a range of 1 to 200 mg / Kg is generally preferred.

  Bone or hematological cancers that can be treated using the present invention include, but are not limited to, primary bone cancers, such as various sarcomas arising from the bone itself, and other types of cancer These include secondary (or metastatic) bone cancer, benign (non-cancerous) bone tumors, and cancers that develop in hematopoietic cells of the bone marrow, also called "blood cancers". Osteosarcoma (also called osteogenic sarcoma) is the most common primary bone cancer. The cancer begins in bone cells and most often occurs in the arms, legs, or pelvic bone. Chondrosarcoma is a carcinoma of chondrocytes, which can occur wherever cartilage is located, most often bones such as the pelvis, leg bones, or arm bones, sometimes trachea, larynx, And on the chest wall. Other sites are the scapula (shoulder blade), ribs, or skull. There are various types of chondrosarcoma that have unique characteristics under a microscope. For example, dedifferentiated chondrosarcoma develops as typical chondrosarcoma, but then some of the tumors are cells of high-grade sarcoma (such as high-grade fibrous histiocytoma, osteosarcoma, or fibrosarcoma) Change into cells like Clear cell chondrosarcoma is rare, grows slowly, and rarely spreads to other parts of the body unless it has returned to its original location several times. Mesenchymal chondrosarcoma can grow rapidly but, like Ewing tumors, is sensitive to radiation and chemotherapy.

  Ewing tumors (also called Ewing sarcomas) are another common primary bone cancer found especially in children, adolescents, and young adults. Most Ewing tumors occur in bone, but they can occur in other tissues and organs. The most common sites for this cancer are the pelvis, chest wall (such as ribs or scapula), and long bones in the legs or arms.

  Malignant fibrous histiocytoma (MFH) often occurs in soft tissues (connective tissues such as ligaments, tendons, fat, muscle, etc.), also known as anaplastic pleomorphic sarcomas. When MFH occurs in bone, it usually affects the legs (often around the knees) or arms. It tends to grow mostly locally, but can also spread to distant locations such as the lungs.

  Fibrosarcoma is another type of cancer that occurs more often in soft tissue than in bone, and often affects the legs, arms, and jaw bones.

  Giant cell tumors of the bone are a type of primary bone tumor that is benign and malignant in form, and more often benign. Giant cell tumors typically affect the bones of the legs or arms in young and middle-aged adults and do not spread frequently to distant sites, but tend to recur at the site where they developed after surgery There is.

  Chordomas are primary tumors of the bone that usually occur at the base of the skull and in the bones of the vertebrae, do not spread much to other parts of the body, but do not recur in the same area if they are not completely removed. Often there. Lymph nodes, lungs, and liver are the most common areas of secondary tumor spread.

  Spindle cell sarcomas are very similar to osteosarcomas, but do not produce the bone material called bone-like material. There are several types of spindle cell sarcomas, including anaplastic osteosarcoma, malignant fibrous histiocytoma, fibrosarcoma, and leiomyosarcoma.

  Another type of cancer, sometimes called "bone cancer," occurs in hematopoietic cells of the bone marrow rather than the bone itself. The most common cancer that begins in the bone marrow and causes bone tumors is called multiple myeloma. Another cancer that occurs in the bone marrow is leukemia, which is generally considered a blood cancer rather than a bone cancer. Lymphomas that often occur in the lymph nodes can occasionally occur in the bone marrow. Non-Hodgkin's lymphoma generally occurs in the lymph nodes, but occasionally in the bones. Hodgkin's lymphoma develops in the lymphatic system from cells called lymphocytes and is characterized by the presence of abnormal lymphocytes called Reed-Sternberg cells (or B lymphocytes).

  Benign (non-cancerous) cartilage tumors are more common than malignant ones. These are called endochondromas. Another type of benign tumor with cartilage is a cartilage-covered bone process called osteochondroma. These benign tumors rarely turn into cancer. Cancer is slightly more likely to occur in people who have many of these tumors, but this is not yet common. Benign tumors do not spread to other tissues and organs and are usually not life threatening. These are generally healed by surgery. Types of benign bone tumors include, but are not limited to, osteoid osteomas, osteoblastomas, osteochondromas, endochondromas, and cartilage myxofibromas.

  The therapeutic methods disclosed herein may be used to treat other rare blood system cancers or disorders such as pediatric acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML), hairy cell leukemia, juvenile It can also be used for myelomonocytic leukemia (JMML), myelodysplastic syndrome, myelofibrosis, myeloproliferative neoplasm, polycythemia vera, and thrombocythemia.

  Reference to `` bone cancer '' herein also includes metastatic lesions of solid tumor cancers that spread to bone from somewhere else, such as breast, prostate, and lung cancers, and in these populations Have a very high rate of these metastases (estimated 70%, 90% and 40% respectively in the metastatic population). Cells of these types of cancer do not look or act like bone cancer cells, even if they are lesions in the bone. Because these cancer cells still act like primary cancer cells, they still need to be treated with drugs that are usually used for primary cancer. The phosphaplatin complexes disclosed herein can be prepared as previously disclosed (see, for example, US Pat. Nos. 7,700,649 and 8,034,964, and US 2013/0064902 A1). That these complexes, when used for the treatment of all these other cancers, have been shown to be effective treatments for various types of cancer. Can be used to treat or prevent bone cancer. Thus, as used herein, the phrase “cancer that metastasizes to bone” refers to any cancer that has spread or spread to bone structure, including but not limited to breast, prostate, and lung cancer. A type of cancer.

  In some embodiments, the methods of the invention may be preferably used in combination with other therapies, such as stem cell transplantation, chemotherapy in combination with other anticancer agents, and / or radiation therapy.

  The following non-limiting examples further illustrate certain aspects of the present invention.

Example 1
Assay of R, R-Pyrodac-2 on Multiple Myeloma Cell Lines The compound trans- (R, R) -1,2-cyclohexanediamine- (dihydrogen pyrophosphato) platinum (II) ("R, R-Pyrodac-2"") Were tested against two multiple myeloma cell lines RPMI8226 and MM1R. The IC50 values of R, R-pyrodac-2 for cell lines RPMI8226 and MM1R were found to be 2.90 μM and 2.78 μM, respectively, demonstrating the potency and activity of this compound.

Example 2
Test Background of R, R-Pyrodac-2 on Multiple Myeloma Mouse Model Transpirodac-2 compound was successfully used to predict the clinical activity of the drug in multiple myeloma mouse models, especially in untreated and relapsed MM Test on Vk * MYC mice reported to be a clinical model (Chesi, M., et al., Cancer Cell, 2008, 23, 167-180; Chesi, M., et al., Blood). , 2012, 120 (2): 376-385). In addition, the trans-pyrodac-2 compound was tested in mice transplanted with the more aggressive bortezomib-resistant Vk12598 and multidrug-resistant Vk12653 lines, both of which were generated from Vk * MYC mice.

Materials and Methods De novo Vk * MYC mice were aged for more than one year and M spike levels were monitored. After the predominant concentration of M spikes reached a level between about 10-70 g / L (estimated by densitometry, M spikes compared to albumin), mice were candidates for initiating drug treatment. Was. Mice brought into this study were given (R, R) -pyrodac-2 at a concentration of 100 or 67 mg / kg, respectively, twice a week via IP injection after preparation in phosphate buffer (IP). n = 2) or three times a week (n = 1). M spike levels were measured weekly and post-treatment measurements were compared and normalized to pre-treatment baseline measurements. Dosing was stopped after 2 weeks of treatment.

  In addition, mice were transplanted with the Vk12598-transplantable line and received vehicle (n = 11) or (R, R) -pyrodac-2 (n = 12) at a concentration of 62.5 mg / kg. Mice implanted with the Vk12653 implantable line were similarly treated with vehicle (n = 10) or 62.5 mg / kg of (R, R) -pyrodac-2 (n = 10). Both Vk12598 and Vk12653-transplanted mice were treated twice weekly for 2 weeks via IP injection and monitored via survival and M spike levels, respectively.

Results Results from de novo Vk * MYC mice are shown in FIG. 1 and illustrate that treatment with (R, R) -Pyrodac-2 resulted in> 50% reduction of M spikes at 2 weeks. However, it has passed a statistically correlated activity threshold indicating robust activity in human MM patients for the drugs tested in this model. At this point, treatment was discontinued and M spike levels continued to decline for 1-2 weeks (see "PT-112 best response" in Figure 1), with the lowest M spike at 19% of baseline 11 days after treatment discontinuation. Was observed. These results were comparable or better than those produced by treatment with the approved MM SoC agent.

  FIG. 2 shows the results from Vk12598-transplanted mice (A) and Vk12653-transplanted mice (B). In the case of Vk12598-transplanted mice, treatment with (R, R) -Pyrodac-2 resulted in a significant increase in survival and sustained for 6 months compared to a vehicle control group in which all mice died by day 21. Produced numerous durable complete reactions. Furthermore, (R, R) -Pyrodac-2 treatment caused a statistically significant reduction in M spike levels compared to the vehicle control group in Vk12653-transplanted mice.

Conclusion (R, R) -Pyrodac-2 was well tolerated when administered twice or three times a week in the Vk * MYC mouse model. Both doses were effective in reducing M spike levels to less than 50% after 2 weeks of treatment. In addition, (R, R) -pyrodac-2 treatment was active in both Vk12598 and Vk12653 mice, as indicated by increased survival and suppression of elevated M spike levels, respectively. Taken together, in light of previous studies in this model demonstrating a correlation between activity in the Vk * MYC model and clinical activity in human patients, these data indicate that (R, R) -Pyrodac-2 is highly frequent. Suggests that it is effective in treating human patients with multiple myeloma.

Example 3
Assay of Platinum Distribution in R, R-Pyrodac-2 Treated Mice Materials and Methods Five CD-1 mice were administered intravenously (IV) with (R, R) -pyrodac-2 at a concentration of 90 mg / kg, The other mouse was administered with the vehicle (phosphate buffer). After dosing, (R, R) -Pyrodac-2 treated mice were euthanized at different time points (45 minutes, 3, 12, 24, and 72 hours) and control mice were euthanized 45 minutes after dosing. I let it. Subsequently, the carcasses were flash frozen at -70 ° C. Whole body sagittal section slides were prepared for control, 45 minute, and 24 hour mice. The slides were then scanned for the concentration of Pt (atomic component of (R, R) -pyrodac-2) across the whole body cross section using laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS). Additional slides were prepared from adjacent locations and stained with hematoxylin and eosin (H & E) to map Pt signals to various organs and tissues.

Results At T45 min and T24 h, good detection of Pt was observed in tissue sections mounted on indium tin oxide (ITO) slides in treated sections (Table 1). An LA-ICP-MS image of the screened area (white bar) of the mice treated with (R, R) -Pyrodac-2 after 24 hours is shown in FIG. 3 and the detection of platinum at 24 hours T of the treated liver (raw data) Is shown in FIG.

Conclusions Good detection of Pt was observed at k = 3 and k = 10 in various organs, in both treated tissues, respectively, beyond the limits of detection and quantification as defined in the IUPAC Gold Book .

  Pt levels in all organs of control animals are statistically significant and below Pt levels in corresponding organs of exposed animals.

LA-ICP-MS Imaging Objective To detect platinum element (Pt) by LA-ICP-MS imaging on whole mouse sections with 150 μm spatial resolution covering whole sections of various sections of animals: 45 minutes treatment 24 hours of treatment and 45 minutes of control (3 sectioning levels per animal).

Mice were sectioned at a thickness of 20 μm on three different section surfaces using a protocol cryostat and mounted on ITO glass slides. See FIG.
● Level 1: sagittal section through the left side of the left eye of the mouse. ● Level 2: second sagittal plane on the right side of the left eye passing through the largest major organ.
• Level 3: The third sectioning level in the sagittal midline plane of the animal.

The target area was defined as follows.
● Priority 1: Bone (vertebra, pelvis, ribs, femur), liver, kidney.
● Priority 2: Lung, spleen, heart, brain, thyroid, thymus.

  The slides were lyophilized for 30 minutes and then stored at -80 C until further use. Slides were vacuum dried at room temperature for 30 minutes before ICP-MS imaging. Higher resolution images were also collected, focusing on the bone containing area.

Analysis For tissue sections, analysis was performed by LA-ICP-MS 2D.

Results Calibration was performed in a concentration range of 10-5000 nM using a minimum of six non-zero concentrations to generate a calibration curve. Good linearity of Pt was observed by spotting the calibration standard on liver control tissue sections (FIG. 6).

  The results for distribution and quantification from ICP-MS imaging are listed in Table 2. ICP-MS imaging results of platinum in the T45 min mouse section plans 1, 2, and 3 are shown in FIGS. 7, 8, and 9, respectively. A cross-sectional view from time T24 is shown in FIG. 10, and high-resolution images of various bone-containing regions from T45 are shown in FIG. Note: The "diffusion" effect observed in some tissue sections is not due to platinum delocalization, but rather the effect of rinsing material in the ablation cell. This occurs on all LA-ICP-MS systems for concentrated areas where the system can achieve 1-2 digit signal drop every 50 ms.

  In control samples, negligible Pt (about 100 nM) was detected and low levels of Pt were detected in intestine and stomach. At T = 45 min, Pt was most prominently concentrated in bone (> 200 μM), but significant amounts were also detected in other places such as kidney, lung, and liver. At T = 24 hours, the highest Pt signal originated from bone tissue, albeit at a lower concentration (<3 μM) than was observed at T45 minutes.

Conclusion Among other target tissues, (R, R) -Pyrodac-2 (or Pt from (R, R) -Pyrodac-2) is clearly concentrated in the bone compartment at very high concentrations over a long period of time. This is hypothesized to be due to the pyrophosphate content of the molecule. In vitro where (R, R) -pyrodac-2 was tested in several different cancerous cell lines, including leukemia cell lines and multiple myeloma cell lines resistant to lenalidomide, dexamethasone, and / or bortezomib In experiments, typically low micromolar concentrations were sufficient to kill cancer cells. Thus, these bone tissues are exposed to (R, R) -pyrodac-2 (or derived Pt) at much higher concentrations than are normally required to induce cancer cell death. This probably explains the high activity of (R, R) -Pyrodac-2 in the multiple myeloma Vk * MYC mouse model, where (R, R) -Pyrodac-2 is localized to bone Suggests that it is particularly effective in combating

Example 4
Background of the Decrease in Clinically Active Prostate-Specific Antigen (PSA) of R, R-Pirodac-2 in Patients with Metastatic Castration-Resistant Prostate Cancer (mCRPC) Background In an ongoing Phase I solid tumor dose escalation study, -2 (PT-112), 1 day 28 day cycle, day 8, and day 15 were given mCRPC patients 63 years of age at a dose of 200 mg / ^{m 2.}

RESULTS This severely previously treated metastatic patient experienced a sharp drop in PSA after treatment began. After less than a full cycle of treatment, the reduction in PSA was about 80%. The PSA measurements from this patient are shown in FIG.

Conclusion R, R-Pyrodac-2 is very active in this mCRPC patient. This activity can be explained in part by the high drug concentration at the site of metastatic bone disease.

Background of Decreased Serum Alkaline Phosphatase Levels In an ongoing phase I solid tumor dose escalation study, R, R-pyrodac-2 (PT-112) was administered on days 1, 8, and 15 of a 28-day cycle. in, it was administered to mCRPC patients 71 years of age at a dose of 250 mg / ^{m 2.} The patient participated in a study involving elevated serum alkaline phosphatase levels, a sign of metastatic bone disease.

Results At the start of treatment, the patient experienced a rapid decrease in serum alkaline phosphatase levels, which was an indication of anticancer drug activity in cancerous bone lesions. The measured values of alkaline phosphatase from this patient are shown in FIG. These measurements were subdivided to verify the percentage of results (vs. liver) emanating from bone. Bone percentage accounts for the majority of the results, confirming its association with metastatic bone disease in this patient.

Conclusion R, R-Pyridac-2 was very active in this patient with mCRPC, as indicated by a sharp drop in serum alkaline phosphatase levels. This example serves as further evidence of the activity of R, R-pyrodac-2 against cancers located in or on bone.

Example 5
Background of the Clinical Activity of R, R-Pyrodac-2 in Bone Disease Sites of Metastatic Basal Cell Carcinoma (mBCC) Patients In an ongoing phase I solid tumor dose escalation study, R, R-pyrodac-2 (PT-112 ) for 1 day 28 day cycle, was administered on day 8, and day 15 to mBCC patients 63 years of age at a dose of 150 mg / ^{m 2.}

Results Positron emission tomography (PET) imaging showed metastasis to the right side of the sacrum as indicated by a drop in the standard update (SUV) from 10.2 to 3.8 after two cycles of treatment. A significant decrease in signal intensity at the osteosynthesis site was revealed. The two PET images at baseline and after the cycle are in FIG. 14 below.

Conclusion R, R-pyrodac-2 demonstrates high activity at this site of bone disease, especially in the treatment of cancer where R, R-pyrodac-2 is present in or on bone tissue. Supports the argument that it is powerful and active. Furthermore, the maximum tolerated dose (MTD) has not yet been determined in this study, a dose of 150 mg / ^{m 2} is well below the highest dose that is considered safe for 360 mg / ^{m 2,} bone These anti-cancer effects at the site of the disease can occur at very well tolerated doses.

  The foregoing non-limiting examples and embodiments have been set forth to illustrate certain aspects of the present invention. Those skilled in the art will appreciate that various changes or modifications can be made without departing from the spirit and scope of the invention. All references mentioned herein are incorporated by reference in their entirety.

Claims (15)

A method of treating a subject having bone cancer or blood cancer, or cancer that metastasizes to bone, comprising a therapeutically effective amount of a phosphaplatin compound having a structure of Formula I or II,
Or administering a pharmaceutically acceptable salt thereof to said subject, wherein R ¹ and R ² are each independently NH ₃ , a substituted or unsubstituted aliphatic amine, and a substituted or unsubstituted The method, wherein R ³ is selected from a substituted or unsubstituted aliphatic diamine and substituted or unsubstituted aromatic diamine. R ¹ and R ² are each independently selected from NH ₃ , methylamine, ethylamine, propylamine, isopropylamine, butylamine, cyclohexaneamine, aniline, pyridine, and substituted pyridine, and R ³ is 1,2- The method according to claim 1, wherein the method is selected from ethylenediamine and cyclohexane-1,2-diamine. The phosphaplatin compound,
2. The method of claim 1, wherein the method is selected from the group consisting of pharmaceutically acceptable salts, and mixtures thereof.   The phosphaplatin compound is (R, R) -1,2-cyclohexanediamine- (dihydrogen pyrophosphato) platinum (II) (or “PT-112”), or a pharmaceutically acceptable salt thereof; The method of claim 1. A method of treating a subject having bone cancer or blood cancer, or cancer that metastasizes to bone, comprising a therapeutically effective amount of a phosphaplatin compound having a structure of Formula III or IV,
Or administering a pharmaceutically acceptable salt thereof to said subject, wherein R ¹ and R ² are each independently NH ₃ , a substituted or unsubstituted aliphatic amine, and a substituted or unsubstituted The method, wherein R ³ is selected from a substituted or unsubstituted aliphatic diamine and substituted or unsubstituted aromatic diamine. R ¹ and R ² are each independently selected from NH ₃ , methylamine, ethylamine, propylamine, isopropylamine, butylamine, cyclohexaneamine, aniline, pyridine, and substituted pyridine, and R ³ is 1,2- The method according to claim 4, wherein the method is selected from ethylenediamine and cyclohexane-1,2-diamine. Monomeric platinum (IV) pyrophosphate complex has the formula (IV), wherein, ^{R 3} is 1,2-ethylene - a diamine or cyclohexane-1,2-diamine, according to claim 4 Method. The phosphaplatin compound,
6. The method of claim 5, wherein the method is selected from the group consisting of pharmaceutically acceptable salts, and mixtures thereof.   The method of any one of claims 1 to 7, wherein said administering comprises an intravenous or intraperitoneal injection.   10. The method of any one of claims 1-9, wherein the dose of the platinum pyrophosphate complex is in the range of about 1 mg to about 200 mg / kg based on the subject's body weight.   The bone cancer or blood cancer is osteosarcoma, chondrosarcoma, Ewing tumor, malignant fibrous histiocytoma (MFH), fibrosarcoma, giant cell tumor, chordoma, spindle cell sarcoma, multiple myeloma, non-Hodgkin Lymphoma, Hodgkin's lymphoma, leukemia, pediatric acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML), hairy cell leukemia, juvenile myelomonocytic leukemia (JMML), myelodysplastic syndrome, myelofibrosis The method of any one of claims 1 to 10, wherein the method is selected from the group consisting of: myeloproliferative neoplasm, polycythemia vera, and thrombocythemia.   The bone cancer or blood cancer is osteosarcoma, chondrosarcoma, Ewing tumor, malignant fibrous histiocytoma (MFH), fibrosarcoma, giant cell tumor, chordoma, spindle cell sarcoma, multiple myeloma, non-Hodgkin 12. The method of claim 11, wherein the method is selected from the group consisting of lymphoma, Hodgkin's lymphoma, and leukemia.   The method according to any one of claims 1 to 12, wherein the method further comprises administering a second anticancer agent to the subject.   14. The method of claim 13, wherein the second anticancer agent is selected from the group consisting of an alkylating agent, a glucocorticoid, an immunomodulator (IMiD) and a proteasome inhibitor.   (R, R) -1,2-cyclohexanediamine- (dihydrogen pyrophosphato) platinum (II) (or "PT") in the manufacture of a medicament for the treatment of bone cancer or blood cancer or cancer that metastasizes to bone. -112 "), or a pharmaceutically acceptable salt thereof.